Synthesis of quinolines and acridines by the reaction of 2-(perfluoroalkyl)anilines with lithium and Grignard reagents

Introduction

An unconventional synthetic route to quinolines and acridines involves ionization of 2-(perfluoroalkyl)aniline or an analogue followed by elimination of fluoride from the resultant anion and then intramolecular or intermolecular cyclization of thus generated non-aromatic intermediate product. Large series of new quinolines and acridines have been synthesized by using this methodology and tested for diverse biological activity. Studies have shown that substituted quinolines, acridines, and analogues are anti-HIV-1 agents [1–3]. Since a statistically significant correlation between binding of these compounds to double-helical regions of RNA and biological activity was found, it was suggested that the mechanism of action of the active agents involves intercalation with RNA [2]. This subject has been reviewed [4]. Subsequently, it has been found that 2-arylquinolin-4-amines can intercalate with double- and triple-helical DNA. Importantly, it has been demonstrated that compounds can be designed for selective stabilization of triplex DNA in the presence of duplex DNA [5–13]. Additional studies have shown that certain quinolines and acridines are antagonists of immunostimulatory bacterial DNA [14–17] and, as such, can induce remissions of the rheumatoid arthritis and systemic lupus erythematosus. These most recent biological studies have been mentioned in the particular synthetic papers and complete reviews will be published in due course.

2-(Perfluoroalkyl)anilines

These starting materials 2 (Scheme 1) are inexpensive commercial products or can easily be prepared by perfluoroalkylation of 2-haloanilines 1 or anilines 3 [18–21]. Interestingly, the trifluoromethylation of 3 is ortho-regioselective [21]. Common substituents R¹ are well tolerated in the preparation of 2. The perfluoroalkyl group can be introduced at position 2 of heteroaromatic amines by using an analogous approach [21]. A different preparation of 3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine [22, 23] involves reductive cyclization of 2-fluoro-3-(trifluoroacetyl)pyridine by treatment with hydrazine (not shown). The heteroaromatic analogues of 2 can undergo transformations that are similar to the syntheses of quinolines and acridines discussed below. The recently developed oxidative trifluoromethylation of aryl boronic acids by the reaction with (trifluoromethyl)trimethylsilane in the presence of a copper catalyst has yet to be adapted to the synthesis of substrates 2 [24–27].

Scheme 1

Synthesis of quinolines

This section pertains to synthesis of 2-arylquinolines that are substituted at position 4 with a functionalized amino or alkoxy group. The classical synthetic routes to these relatively simple compounds are cumbersome, especially at the workup step, and are limited to the preparation of a small number of derivatives. By contrast, the synthetic routes to 2-arylquinolines, which are based on the chemistry of the anionically activated 2-(trifluoromethyl)anilines 2 or their ketimines, are experimentally simple, efficient, and allow for the introduction of a variety of functionalities at the 2-arylquinoline system (Scheme 2). There are two approaches to the construction of the quinoline ring system with 2 as the substrate. The first methodology is illustrated by the synthesis of 2-aryl-4-fluoroquinoline 6 by the reaction of 2 with lithium enolate of aryl methyl ketone [28, 29]. Briefly, the anion derived from 2 undergoes elimination of fluoride, and then the resultant non-aromatic intermediate product 4 is aromatized by the addition reaction with enolate anion to generate 5. Quinoline 6 is produced by intramolecular cyclization of 5 followed by aromatization of the cyclized intermediate product. Nucleophilic displacement of fluoride in 6 provides an easy access to 4-substituted quinolines 11.

Scheme 2

Alternatively, quinolines 11 can be efficiently synthesized by base-mediated cyclization of ketimines 7 that are obtained by condensation reaction of 2 with aryl methyl ketones [30, 31]. The resulting quinolines 11 derived from 7 contain either an amino or an oxygen function in position 4, depending on the nature of the strong base utilized for cyclization (lithium alkylamide, lithium dialkylamide, or potassium alkoxide). The mechanistic pathway involves a series of internal nucleophilic processes that generate intermediate products 8–10. It is the adduct 10 that undergoes intramolecular 6π-electron cyclization, as evidenced by the isolation and characterization of intermediate 4,4-disubstituted-3,4-dihydroquinoline [30]. The two methodologies discussed above are quite general in scope, and a large array of other substituted quinolines [29, 32–38] and fused quinolines including acridines [39, 40] can easily be prepared by the reaction of 2 or 7 with various basic/nucleophilic reagents [41–45].

A facile amination of fluorophenyl-substituted quinolines provides an important means for the synthesis of aminophenyl-substituted quinolines. For example, the ortho-fluorine atom in a 2,4-difluorophenyl derivative 13, obtained by treatment of ketimine 12 with a lithium alkylamide, is displaced by the reaction with a lithium alkylamide or lithium dialkylamide to give 15 (Scheme 3). This nucleophilic displacement proceeds with absolute regioselectivity. A subsequent ipso displacement of the remaining fluorine atom in 15, upon treatment for an extended period with a dialkylamide reagent, produces 16. The facility of the amination is in the order 2-F>4-F, and it is additionally exemplified by a direct preparation of a 2-(2-aminophenyl)quinoline derivative 14 upon treatment of ketimine 12 with a lithium dialkylamide reagent. The facile regioselective displacement of the ortho-fluorine atom in the presence of other fluorine atoms at the phenyl group is explained in terms of a complex induced proximity effect process [46, 47].

Scheme 3

A greatly improved preparation of quinolines is illustrated in Scheme 4 [17]. The desired compounds 29–43 were synthesized by condensation of 2-(trifluoromethyl)anilines 17–21 with aryl methyl ketones 22–27 followed by cyclization of the resultant ketimines 28 by treatment with a lithium derivative of 2-(dimethylamino)ethylamine. Previously, this general methodology called for the use of analytically pure intermediate ketimines 28. It was found that prepurification by a simple bulb-to-bulb distillation, giving 28 of about 90% purity, was adequate for the subsequent cyclization. In addition, tetrahydrofuran was used instead of diethyl ether as solvent in the cyclization reactions of 28, which resulted in slightly increased yields of the quinoline products. As can be seen from Scheme 4, many substituents at substrates 17–27 are tolerated to give the corresponding substituted quinolines 29–43.

Scheme 4

Synthesis of quinolines described above is based on the chemistry of anionically activated trifluoromethyl group (n=1 in 2, Scheme 1). As shown in Scheme 2, the quinoline system construction is achieved by an intermolecular cyclization of aniline 2 with lithium enolate or by base-mediated intramolecular cyclization of the corresponding ketimine (Schemes 2 and 4).

Similar transformations of higher 2-(perfluoroalkyl)aniline 2 (n>1) furnish 4-(perfluoroalkyl)quinolines in which the perfluoroalkyl group (C_n-1F_2n-1) is shorter by one carbon atom than that in the starting aniline (C_nF_2n+1). These reactions are exemplified in Scheme 5 by the synthesis of 4-(perfluoropropyl)quinolines 44–47 by treatment of 2-(perfluorobutyl)aniline (2, n=4, R¹ = H) with various lithium enolates of ketones and by LDA-mediated electrocyclization of the corresponding ketimines 48 and 49 [32].

Scheme 5

Synthesis of acridines

Base-mediated cyclization of a ketimine derived from 2-(trifluoromethyl)aniline (2, n=1) and an acyclic ketone furnishes a quinoline, as discussed above, but a 1,2,3,4-tetrahydroacridine 51 [31] is produced in a similar transformation of a cyclohexanone derivative 50 (Scheme 6). Tetrahydroacridines 52 [39] and 53 [2] are obtained in a similar manner using the corresponding cyclic ketones. These products are formed in the presence of a lithium alkylamide used as a base and a nucleophile.

Scheme 6

An entirely different reaction is observed upon treatment of the same substrate 2 with phenyl magnesium bromide or chloride that is substituted at position 2 with a methyl or ethyl group or at positions 2 and 6 with the methyl groups [48]. As exemplified in Scheme 7, the reaction of one molecule of 2 with two molecules of 2-ethylphenylmagnesium bromide (54) yields a substituted acridine 55 that is devoid of the ethyl group from one of the molecules of the Grignard reagent that reacted. In a similar way, the treatment of 2 with 2,6-dimethylphenylmagnesium bromide (56) furnishes an acridine 57, the molecular formula of which is shorter by one carbon atom (methyl group) than that of the molecular combination of one molecule of 2 and two molecules of the starting Grignard reagent.

Scheme 7

Treatment of a higher homologue 2 (n=4) with the same Grignard reagent 56 produces acridine 67 that is devoid of one of the methyl groups of the two molecules of the Grignard reagent required for this reaction (Scheme 8). The reaction is quite general, and a number of substituted 9-perfluoroalkylacridines have been obtained [49, 50]. The pattern is identical in all cases studied: one alkyl group of the two molecules of the ortho-substituted aromatic Grignard reagent is not present in the acridine product, and the 9-(C_n-1F_2n-2)-substituted acridine is produced starting with 2-(C_nF_2n+1)-substituted aniline.

Scheme 8

Mechanism of this unusual acridine synthesis has been investigated in detail [50] and is shown in Scheme 8 for the particular synthesis of acridine 67 by the reaction of 2-(perfluorobutyl)aniline 2 (n=4) with Grignard reagent 56. The first step is deprotonation of the aniline, which generates an anionic intermediate product 58. Elimination of fluoride from the benzylic position of 58 is then followed by nucleophilic addition of the Grignard substrate to the resultant o-quinoid intermediate 59. This reaction gives rise to the aromatic adduct 60, which can undergo another elimination of fluoride in a way similar to the initial reaction mentioned above to give two cis and trans isomers Z-61 and E-61. The aza-ortho-xylylene E-61 (half-life of 6 h at 23°C) has been isolated and characterized by spectral methods [50]. It is suggested that these isomers can undergo equilibration under basic conditions by deprotonation of a methyl group and the intermediary of 63. It is the intermediate product E-62 (magnesium derivative of E-61) that undergoes electrocyclization to generate the non-aromatic acridine derivative 64 (vide infra). The methyl shift in 64 to generate N-methyl derivative 65 concludes the reaction sequence before workup. Quenching the mixture with water followed by oxidation of the resultant dihydroacridine with molecular oxygen generates N-methylacridinium intermediate product 66, which is the direct precursor to the observed acridine 67. As can be seen from Scheme 8, acridine 67 is formed in an S_N2 nucleophilic attack of hydroxide ion on the methyl group of 66. The presumed high reactivity of 66 in nucleophilic substitution reaction is expected because the positive charge of the leaving group (acridine 67) and, therefore, its leaving ability is strongly enhanced by the presence of an electron-withdrawing perfluoroalkyl group. An important result of this analysis is that the mysterious lack of a methyl group in the product is due to removal of this group in the form of a methanol molecule. The reaction leading to 9-arylacridines (Scheme 7) may follow a similar mechanism.